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Clinical use of extracorporeal membrane oxygenation (ECMO) and carbon dioxide removal (ECCO2R) have become well established techniques for the treatment of severe respiratory failure; however they require full cardiopulmonary bypass, representing major procedures with high morbidity. We theorized the possibility of an efficient low flow venavenous extracorporeal membrane gas exchange method. Four mongrel 12kg dogs were submitted to vena-venous extracorporeal membrane gas exchange via a jugular dialysis catheter using a low flow (10 ml/min) roller pump and a membrane oxygenator for a period of four hours. Respiratory rate was set at 4 breaths/min with a FiO2of 21% and ventilatory dead space was increased. Adequate gas exchange was obtained (pO2139, pCO224, Sat 99.4%), without major hemodynamic changes or hematuria. Our results demonstrate the feasibility of a low flow, less aggressive system. Further research should be considered.

The effects of intracoronary administration of histamine on atrial and ventricular contractility were determined in a paced canine isovolumic heart preparation. Contractility was assessed by recording the pressure developed in saline-filled balloons placed in each of the four cardiac chambers. At doses above 0.1 mg and up to 100 mg histamine produced dose-related positive inotropic responses in all chambers. These were preceded by transient negative effects. The positive responses were not affected by a combination of H1 and H2 receptor antagonists antazoline and cimetidine but were almost completely abolished by the beta adrenoceptor, blocker timolol. The negative responses were uninfluenced by either treatment. It was concluded that, in the canine isovolumic heart not subjected to complicating chronotropic and extracardiac factors, moderate doses of histamine are devoid of inotropic effects. Higher doses do produce myocardial stimulation, not mediated by histamine receptors, but probably due to norepinephrine release. These responses are preceded by transient non-specific depressant effects.

The effects of the stereochemically pure psychoactive cannabinoid (-)-11-OH-Δ8-tetrahydrocannabinol-dimethylheptyl (HU-210) on blood pressure (BP) and heart rate (HR) were determined in rats. In pentobarbitalanesthetized animals, the compound produced doserelated, long-lasting hypotension and bradycardia at doses between 10 and 1,000 μg/kg. BP began to decrease immediately after drug administration, and in no case was an initial pressor response observed. Previous vagotomy (VX) or pretreatment with 6-hydroxydopamine (6-OHDA) did not affect hypotension. Bradycardia was inhibited by VX, but only 60 min after administration of HU-210; it was enhanced by 6-OHDA. The cannabinoid blocked reflex bradycardia induced by phenylephrine (PE). HU-210 also decreased BP and HR in conscious rats. Hypotension lasted 2 h, whereas bradycardia was still present 8 h after drug administration. HU-210 thus shares with Δ9-tetrahydrocannabinol (THC) the ability to decrease BP and HR, but is 5-10 times more potent than the natural compound. Its lack of an initial pressor effect, such as that described for THC, could be related to its specificity for the type-1 cannabinoid (CB1) receptor. Hypotension and bradycardia after HU-210 administration are not due to sympathetic withdrawal. Enhanced parasympathetic tone is involved in bradycardia only at a late stage of the response.

The influence of isoniazid (ISO) preincubation on the relaxant effects of a group of nitrovasodilators was examined in norepinephrine-contracted rat aortic rings with and without endothelium. ISO displaced to the left the dose-response curves to all nitrovasodilators and increased the negative logarithm of their median effective concentration (EC50) values. Potentiation was minimal with sodium nitrite and increased progressively with sodium nitroprusside, nitroglycerin (NTG), and isosorbide dinitrate. The phenomenon occurred in rings with and without endothelium and was not seen with the nitric oxide-releasing agent acetylcholine or with the nonspecific vasodilator hydralazine. These results confirm previous observations of potentiation of NTG vasorelaxation by ISO and extend them to other nitrovasodilators. Potentiation is attributed to the previously postulated inhibition by ISO of pyridoxal-requiring enzymes involved in the breakdown of homocysteine, leading to its intracellular accumulation. Increased availability of this sulfhydryl donor would lead in turn to enhanced bioactivation and vasorelaxant effects of nitrovasodilators. The different degrees of potentiation observed would be related to the sulfhydryl requirement of each compound for bioactivation. Alternatively, enhanced bioactivation of the nitrovasodilators could be due to induction by ISO of P-450 enzymes involved in this process.

The effects of intra-arterial infusions of serotonin on internal and external carotid blood flow were determined in anesthetized dogs by electromagnetic flow measurements. Serotonin decreased flow in the internal carotid and increased it in the external carotid. Both responses were blocked by the serotonin antagonist methysergide. The alpha adrenergic antagonist zolertine, the ganglionic blocking agent chlorisondamine and the vasodilator diazoxide blocked external carotid dilator responses but did not modify constriction in the internal carotid. Blockade of external carotid responses by the three drugs was also demonstrated in experiments in which this bed was perfused at a constant rate. These results indicate that the internal and external carotid vascular beds of the dog react in opposite ways to serotonin, that both responses are mediated through the same type of serotonin receptors and that the dilator responses of the external carotid are dependent on vascular tone.

In order to evaluate the relation between hypotension induced by hydralazine and the resultant reflex tachycardia, as well as the role of baroreflex sensitivity in determining the magnitude of these responses, the drug was administered orally at a dose of 1 mg/kg to a group of trained conscious normotensive and renal hypertensive dogs. Responses were assessed by measuring blood pressure and heart rate for 8 hr after dosing and integrating the changes observed over time in order to obtain a mean value. Baroreflex gain was calculated as the ratio of heart rate to blood pressure responses. Hypotension was greater in hypertensives, whereas tachycardia was not different between groups. Gain was therefore smaller in hypertensives, but not uniformly so, a portion of these animals having values within the normotensive range. This high gain group responded with less hypotension and more tachycardia than did the low gain group. Differences in pressure and rate responses to repeated administration of hydralazine between the two groups were minimal. It is suggested that baroreflex gain, an innate individual characteristic, is an important determinant of acute pressure responses to hydralazine in dogs, hypertensive animals having less gain than normotensives and showing increased hypotensive responses. Gain appears not to be as important in determining the chronic effects of the drug.

After the observation that in anesthetized rats the antitubercular agent isoniazid potentiates the hypotensive effect of the vasodilator hydralazine (H) and transforms the accompanying reflex tachycardia to bradycardia, a number of hydrazine (HYD) derivatives were tested for this interaction in pentobarbital-anesthetized rats. All HYDs studied elicited this response in varying degrees, isoniazid, thiosemicarbazide and thiocarbohydrazide being the most active. Experiments were then carried out to explore the possibility of an influence of the HYDs on reflex reactions to H due to interaction with pyridoxal, inhibition of glutamic acid decarboxylase and decreased levels of brain gamma-aminobutyric acid. Although the H-HYDs interaction was prevented by vagotomy, it was unaffected by exogenous pyridoxal, did not occur with the alpha adrenergic antagonist prazosin and was not mimicked by non-HYD pyridoxal reactors. In other experiments, pharmacokinetic interactions and monoamine oxidase inhibition were ruled out as alternative explanations for this phenomenon. It was concluded that the H-HYDs interaction is not related to a possible influence of these drugs on central gamma-aminobutyric acid cardiovascular regulation and that other presently unknown mechanisms are involved.

Dogs receiving mecamylamine on chronic oral administration were found to develop consistently and significantly high blood pressure, following tolerance to the initial hypotensive action of the drug. It is suggested that the feedback mechanisms might be involved in this effect.